Even though significant advances have occurred in the treatment of cancer, it still remains a major health concern. Cancer has been reported as the leading cause of death in the United States with one of every four Americans likely to be diagnosed with the disease.
Included among the known chemotherapeutic drugs are carmustine, doxorubicin, methotrexate, paclitaxel, cyclophosphamide, procarbazine, and vinblastine, to name only a few. However, many chemotherapeutic drugs also produce undesirable side effects in the patient.
Certain nonsteroidal anti-inflammatory drugs (NSAIDs) have been recognized to have broad anticancer activity in animal models alone and in combination with chemotherapy or radiation. Representative examples include: Hial et al., “Alteration of tumor growth by aspirin and indomethacin: studies with two transplantable tumors in mouse” Eur. J. Pharm. 37: 367-376, 1976; Lynch et al., “Mechanism of inhibition of tumor growth by aspiring and indomethacin” Br. J. Cancer 38: 503-512, 1978; Bennett et al., “Increased survival of cancer-bearing mice treated with inhibitors of prostaglandin synthesis alone or with chemotherapy” Br. J. Cancer 45: 762-768, 1982; Pollard and Luckert “Prolonged antitumor effect of indomethacin on autochthonous intestinal tumors in rats” J. Natl. Cancer Inst. 70: 1103-1105, 1983; Fulton, “Inhibition of experimental metastasis with indomethacin: role of macrophages and natural killer cells” Prostaglandins: 35: 413-425, 1988; Moorghen et al., “The effect of sulindac on colonic tumor formation in dimethylhydrazine-treated mice” Acta histochemica 29: 195-199, 1990; and Moorghen et al., “A protective effect of sulindac against chemically-induced primary colonic tumours in mice” J. of Path. 156: 341-347.
Sulindac (Clinoril™) is a NSAID that has demonstrated anticancer activity. It has been recognized as having benefits for treating dysplasia as evidenced by a number of clinical trials in familial adenomatous polyposis patients which have shown the ability of sulindac to cause the regression of existing adenomas (size and number) and inhibit new adenoma (polyp) formation. For example, see Waddell et al, “Sulindac for polyposis of the colon”. J. of Surg. 157: 175-179, 1989; Labayle et al., “Sulindac causes regression of rectal polyps in familial adenomatous polyposis” Gastroenterology 101: 635-639, 1991; Nugent et al., “Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis” Br. J. Surg. 80: 1618-1619, 1993; Giardiello, et al., “Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis” N. Eng. J. Med 328: 1313-6, 1993; and Winde et al., “Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment.” Dis. Colon Rectum 38: 813-830, 1995.
The mechanism responsible for the anti-inflammatory efficacy and as well as the toxicity of NSAIDs and COX-2 selective inhibitors (gastrointestinal, renal, hematological, cardiovascular) has been shown to involve cyclooxygenase (COX)-1 or COX-2 inhibition. Sulindac and certain other NSAIDs also have hepatic toxicity. For instance, see Vane, “Mode of action of aspirin and similar compounds” In Prostaglandin Synthetase Inhibitors, Eds Robinson, Raven Press, New York, N.Y., 1974; Eaker “Gastrointestinal injury related to the use of nonsteroidal anti-inflammatory drugs” Gastrointestinal Disease Today 6: 1-8, 1997; Wolfe et al., “Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs” N. Eng. J. Med 340: 1888-99, 1999; Palmer “Renal complications associated with use of nonsterdoidal anti-inflammatory agents” J. Invest. Medicine 43: 516-533, 1995; Tarazi et al., “Sulindac-associated hepatic injury: analysis of 91 cases reported to the Food and Drug Administration” Gastroenterology 104: 569-574, 1993; and Mukherjee et al. “Risk of cardiovascular events associated with selective COX-2 inhibitors” JAMA 286: 954-959, 2001.
Most investigators attribute the mechanism for the anticancer activity of NSAIDs to anti-inflammatory activity involving COX inhibition, although there is evidence for a COX-independent mechanism as mentioned below. For example, the activity of the sulfone metabolite of sulindac has been described which retains anticancer activity in preclinical and clinical trials but does not inhibit cyclooxygenase and displays less GI toxicity. See for example, Piazza et al., “Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis” Cancer Res. 55: 3110-3116, 1995; Piazza et al., “Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels” Cancer Res. 57: 2909-2915, 1997; Piazza et al., “Apoptosis primarily accounts for the growth inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction” Cancer Res. 57: 2452-2459, 1997; Piazza et al, “Exisulind a novel proapoptotic drug inhibits rat urinary bladder tumorigenesis” Cancer Res., 61: 3961-3968, 2001; and Chan “Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention” The Lancet Oncology 3: 166-174, 2002.
There are publications suggesting that certain chemical modifications to the carboxylic acid moiety of NSAIDs will result in improved safety (i.e., as prodrugs or by localized release of nitric oxide). For example, see Mahmud et al., “A unifying hypothesis for the mechanism of NSAID related gastrointestinal toxicity”. Ann. Rheumatic Diseases 55: 211-213, 1996; Venuti et al., “Synthesis and biological evaluation of (N,N,N,-trialkylammonium) alkyl esters and thioesters of carboxylic acid nonsteroidal anti-inflammatory drugs” Pharmaceutical Research 6: 867-873, 1989; Salimbeni et al., “New esters of N-arylanthranilic acids” Farmaco 30: 276-86, 1975; and Elliot et al. “A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats” Gastroenterology 109: 524-530, 1995.
In addition, U.S. Pat. Nos. 5,401,774, 6,166,053 and 6,200,771 suggest certain modifications to sulindac sulfone which is not a NSAID.
A series of amide and ester derivatives of indomethacin and meclofenamic acid involving modifications to the carboxylic acid moiety were described by Marnett et al. These compounds were described as having safety advantages over the parent NSAIDs based on selectivity for the cyclooxygenase-2 isozyme. However, anticancer activity was not described and modifications to improve anticancer efficacy (potency) were not described. For example, see Kalgutkar et al., “Biochemical based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal anti-inflammatory drugs to potent and highly selective COX-2 inhibitors” Proc. Natl. Acad. Sci. 97: 925-930, 2000; Kalgutkar et al. “Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors” Bioorganic and Medicinal Chemistry Letters 12: 521-524, 2002; Kalgutkar et al., “Ester and amide derivatives of the nonsteroidal anti-inflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors” J. Med. Chem. 43: 2860-2870, 2000; U.S. Pat. No. 5,973,191 to Mamett and Kalgutkar “Selective inhibitors of prostaglandin endoperoxide synthetase-2”; and U.S. Pat. No. 5,475,021 to Marnett and Kalgutkar “Compounds and compositions for inhibition of cyclooxygenase activity”.
It cannot be predicted that chemical modifications to one family of NSAIDs are applicable to another family. For instance, meclofenamic acid belongs to the fenamate family, while sulindac belongs to the acetic acid family of NSAIDs and therefore are not structurally similar to each other. Additionally, not all amide modifications to the carboxylic acid result in increased COX-2 selectivity as demonstrated in this disclosure.
Notwithstanding the advances in treatments for cancer and other diseases there still remains room for improved drugs that are effective for the desired treatment, while at the same time exhibiting reduced adverse side effects.